To date, hypoglycaemic therapy is based on the use of drugs having different mechanism of action (Arch. Intern. Med., 1997, 157, 1802-1817).
Insulin and its analogues represent the most used therapy, recurring to the direct hypoglycaemic action of this hormone.
Other compounds act indirectly by stimulating insulin release (sulphonylureas). A different target of hypoglycaemic drugs is represented by the reduction of glucose intestinal absorption through the inhibition of intestinal glucosidases, or by reducing insulin resistance.
Hyperglycaemia is also treated with gluconeogenesis inhibitors, such as biguanides.
Some words have also stressed out the relationship between gluconeogenesis and fatty acid oxidation.
The membrane bound long-chain acylcarnitine transferases, also known as carnitine palmitoyltransferase (CPT), are widely represented in organs and subcellular organelles (Bieber, L. L. 1988 Ann. Rev. Biochem. 57: 261-83). The well-established role of this category of enzymes is the transport of activated long-chain fatty acids through mitochondrial membranes. In this context, the outer mitochondrial membrane CIT I catalyzes the formation of long-chain acylcarnitines that are transported across the mitochondrial membrane by a specific carrier, and reconverted into long-chain acyl-coenzyme A esters by CPT II, which resides in the inner mitochondrial membrane. Long-chain acyl-CoAs are then oxidised to acetyl-coenzyme A, which activates a key gluconeogenetic enzyme: pyruvate carboxylase.
Other works report that diabetic patients have high blood levels of fatty acids, whose liver oxidative fate gives rise to an increase of acetyl-coenzyme A, ATP and NADH. High availability of these compounds maximally stimulates gluconeogenesis, which is in part responsible of the elevated glucose blood levels in diabetic patients. CPT inhibition indirectly reduces the extent of liver gluconeogenesis, and hence blood glucose levels.
CPT inhibitors have been disclosed in J. Med. Chem., 1995, 38(18), 3448-50 and in the corresponding European patent application EP 0574 355 as potential derivatives with hypoglycaemic activity.
Aminocarnitines N-acylated with —COR residue, wherein R is an aliphatic residue with 1 to 19 carbon atoms are disclosed in WO85/04396 useful for investigating the role of transferases in the body, in particular the specificity of carnitine acyltransferase.
Emeriamine and its analogues are disclosed in EP 0 127 098 and J.Med. Chem. 1987, 30, 1458-1463.
Notwithstanding the mechanism of activity above outlined, to date, drugs inhibiting CPT capable to effectively counteract hyperglycaemia do not exist. For some products, such as tetradecyl glycidic acid, or etomoxir, myocardial hypertrophy have been evidenced as side effects (Life Sci., 1989, 44, 1897-1906).
None of the therapies presently used in clinic is fully satisfying, in particular due to the onset of unwanted side effects, such as severe hyperglycaemia, allergic phenomena, oedema, diarrhoea, intestinal disturbances, kidney toxicity, etc.
The necessity to obtain alternative effective therapies for hyperglycaemia still remains.